mTORC1 to AMPK Switching Underlies beta-Cell Metabolic Plasticity During Maturation and Diabetes

Pancreatic beta cells (beta-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). The molecular mechanisms driving this maturation of beta-cell function remain incompletely understood. Here, we show that the control of cellular signaling in beta-cells fundamentally switches from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this is critical for functional maturation. Moreover, AMPK is activated by the dietary transition taking place during weaning, and this in turn inhibits mTORC1 activity to drive the adult beta-cell phenotype. While forcing constitutive mTORC1 signaling in adult beta-cells relegates them to a functionally immature phenotype with characteristic transcriptional and metabolic profiles, engineering the switch from mTORC1 to AMPK signaling is sufficient to promote beta-cell mitochondrial biogenesis, a shift to oxidative metabolism, and functional maturation. We also show that type 2 diabetes, a condition marked by both mitochondrial degeneration and dysregulated GSIS, is associated with a remarkable reversion of the normal AMPK-dependent adult beta-cell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate beta-cell metabolism may thus offer new targets to improve beta-cell function in diabetes. 1- pancreatic beta-cells mRNA profile of P6 (WT) and P45 (WT) were generated by deep sequencing in triplicate. 2- whole islets from betaTSC1 KO and controls (CTRL) were generated by deep sequencing in duplicate. 3- whole islets from db and control (Control) were generated by deep sequencing in duplicate.